1. Resha M. Putzrath, Ph.D., DABT Health Science Coordinator Risk Assessment Forum, EPA/ORD/NCEA 2005 Toxicology and Risk Assessment Conference The 2005 Cancer Guidelines and Early-Life Supplemental Guidance

2. Major Topics Data before default options Mode(s) of Action as a decision point Weight of Evidence for human carcinogenicity Dose-Response: Nonlinear as well as linear Risk Characterization: More options to explain, e.g., more than one descriptor Susceptible lifestages and populations with emphasis on early-life exposure

3. # of Pages Guidelines for Carcinogen Risk Assessment 140 120 100 80 60 40 20 1976 1986 1996 1999 2005 Draft Draft Final As toxicology and risk assessment advance, the guidelines have grown.

4. Cancer Guidelines 2005 Set forth recommended principles and procedures for assessing cancer risks. Inform EPA decision makers and the public about these procedures. Are meant to be dynamic and flexible. Will be updated by additional supplemental guidance as experience and scientific understanding evolve.

5. Key Features of Cancer Guidelines Analyze data before invoking default options. Framework for mode of action Weight-of-evidence narrative and descriptor replaces the previous alpha-numeric Two-step dose-response process separates 1.modeling the observed data, from 2.extrapolation to lower doses. Linear and nonlinear extrapolations are considered. Differential risks to susceptible populations and lifestages are considered.

6. Supplemental Guidance for Early-Life Exposure 2005 Only apply if:  Mutagenic mode of action for carcinogenesis, and  Chemical-specific data are absent Age-dependent adjustment factors (ADAFs) increase potency for exposure during certain periods of life  Examples provided in Section 6 of Guidance  Implementation memo on web site

7. When all else fails, read the Guidelines and Guidance documents. www.epa.gov/cancerguidelines

8. Cancer Guidelines: Important Definitions  Mode of Action: Key events and processes, starting with the interaction of an agent with a cell, through functional and anatomical changes, resulting in cancer or other health endpoints  Key Event: Empirically observable precursor step that is itself a necessary element of the mode of action or is a biologically based marker for such an element

9. Important Definitions (cont.)  Linear: Low-dose linear approximates a straight line at very low doses  Nonlinear: Refers to threshold models and some nonthreshold models, e.g., a quadratic model

10. What’s New, or May Seem New Data before defaults Mode of action (MOA) framework Epidemiological data emphasized Linear or nonlinear extrapolation - or both

11. What’s New (cont.) Precursor data may be used Risk characterization  When MOA not established, present alternative models “with significant biological support”  Margin of exposure (MOE) option

12. Mode of Action is the key For decision-making and for harmonizing cancer and noncancer risk assessment

13. Use framework in Cancer Guidelines to establish MOA(s) MOA sufficiently supported in animals? MOA relevant to humans? Flag lifestage(s) or population(s) that could be susceptible (based on information about the specific MOA) for dose-response analysis. Use linear extrapolation as a default. Determine extrapolation based on information about specific MOA. Model using MOA or use RfD/RfC method as default. Adjustments for susceptible lifestages or populations are part of the process. No Linearity due to mutagenic MOA MOA can not be determined Nonlinear Yes Linear, but nonmutagenic MOA Use the same linear extrapolation for all lifestages, unless have chemical-specific information on lifestages or populations. Were chemical-specific data available in MOA analysis to evaluate differences between adults and juveniles (more, less, or the same susceptibility)? Develop chemical- specific risk estimates incorporating lifestage susceptibility. Yes Early-life susceptibility assumed. Apply age-dependent adjustment factors (ADAFs) as appropriate to develop risk estimates. No Supplemental Guidance for Early-Life Exposures No further analysis of tumors. Use of MOA Framework

14. Use of MOA Information Assess the relevance of laboratory animal results to human environmental exposures Provide insight into whether the dose- response curve is likely to be linear or nonlinear at low doses Identify susceptible populations and lifestages Quantify the relative sensitivity of laboratory animals and human populations

15. Mode of Action Framework Summary description of the hypothesized mode of action. Identification of key events. Strength, consistency, specificity of association. Dose-response concordance. Temporal relationship. Biological plausibility and coherence. Consideration of the possibility of other MOAs

16. MOA Framework  Description of the hypothesized mode of action  Discussion of experimental support for the hypothesized mode of action  Consideration of the possibility of other modes of action EPA’s framework is consistent with others, e.g., the International Programme on Chemical Safety and by the International Life Sciences Institute.

17. Conclusions about the MOA Is the mode of action sufficiently supported in the test animals? Is the mode of action relevant to humans? Which populations or lifestages can be particularly susceptible to the mode or action? –Question is both qualitative and quantitative –Quantitative differences can be used in the dose- response assessment

18. Epidemiological Data Data from humans preferred Hill “criteria” for causation  As discussed in Surgeon General’s report, for cases when only human data assessed  Are guide, not checklist “None of my nine viewpoints can bring indisputable evidence for or against the cause-and-effect hypothesis and none can be required as a sine qua non. What they can do, with greater or less strength, is to help us to make up our minds on the fundamental question — is there any other way of explaining the set of facts before us, is there any other answer equally, or more, likely than cause and effect?” Hill (1965)

19. Laboratory Animals Conventional cancer bioassays generally can support modeling down to 1–10% As a modeling convention, the lower bound associated with response levels of 1, 5, and 10% can be analyzed, presented, and considered For making comparisons at doses within the observed range, the ED10 and LED10 are also reported and can be used Where practicable, present upper and lower bounds on the central tendency

20. Statistical Significance “A statistically significant response may or may not be biologically significant and vice versa. The selection of a significance level is a policy choice based on a trade-off between the risks of false positives and false negatives.”

21. Weight of Evidence Narrative: a short summary (one to two pages) that explains an agent's human carcinogenic potential and the conditions that characterize its expression Descriptors: provide some measure of clarity and consistency in an otherwise free-form narrative  Are a matter of judgment and cannot be reduced to a formula  Examples are illustrative, NOT a checklist

22. “Users of these cancer guidelines and of the risk assessments that result from the use of these cancer guidelines should consider the entire range of information included in the narrative rather than focusing simply on the descriptor.”

23. Weight-of-Evidence Descriptors Carcinogenic to humans Likely to be carcinogenic to humans Suggestive evidence of carcinogenic potential Inadequate information to assess carcinogenic potential Not likely to be carcinogenic to humans

24. Weight of Evidence Conditions of carcinogenicity: –Route, magnitude, and duration of exposure –Susceptible populations and lifestages Summary of key evidence supporting these conclusions Summary of key default options invoked Summary of potential modes of action

25. Conflicting versus Differing Results “[C]onflicting evidence, that is, some studies provide evidence of carcinogenicity but other studies of equal quality in the same sex and strain are negative. Differing results, that is, positive results in some studies and negative results in one or more different experimental systems, do not constitute conflicting evidence, as the term is used here.”

26. Multiple Descriptors By route of exposure By dose or exposure level When multiple modes of action

27. STEP 1. Model the observed data down to a point of departure (POD) Dose (mg/kg-d) Tumor incidence ? xx % POD Two-step approach to dose-response will encourage the use of more data.

28. Point of Departure (POD) Starting point for subsequent extrapolations and analyses Is the lowest point that is adequately supported by the data “The POD for extrapolating the relationship to environmental exposure levels of interest, when the latter are outside the range of observed data, is generally the lower 95% confidence limit on the lowest dose level that can be supported for modeling by the data.”

29. POD (cont.) SAB (1997) suggested that, "it may be appropriate to emphasize lower statistical bounds in screening analyses and in activities designed to develop an appropriate human exposure value, since such activities require accounting for various types of uncertainties and a lower bound on the central estimate is a scientifically-based approach accounting for the uncertainty in the true value of the ED10 [or central estimate].”

30. POD (cont.) Cancer bioassays, 1–10%; epidemiologic studies, possibly below 1% When good quality precursor data are available and are clearly tied to the mode of action of the compound of interest, models that include both tumors and their precursors may be advantageous for deriving a POD

33. Linear Extrapolation from POD is Appropriate When the agent has a mutagenic mode of action or acts through another mode of action expected to be linear at low doses, or When the data do not establish the mode of action, as default option

34. Nonlinear Extrapolation from POD is Appropriate When there is no evidence of linearity, and When there is sufficient information to support a mode of action that is nonlinear at low doses

35. Uncertainty EPA uses a standard curve-fitting procedure for tumor incidence data Use of different approach should provide an adequate justification and compare with the standard procedure Application of models should be open and transparent

36. Uncertainty (cont.) The risk characterization should therefore include, where practicable,  expected or central estimates of risk,  as well as upper and lower bounds, e.g., confidence limits, based on the POD,  if not a full characterization of uncertainty of the risk. OMB Circular A-4 (2003) emphasizes, “Whenever it is possible to characterize quantitatively the probability distribution, some estimates of expected value... must be provided in addition to ranges, variances, specified low-end and high-end percentile estimates, and other characteristics of the distribution.”

37. Uncertainty (cont.) NRC (1994) saw the need to treat uncertainty in a predictable way that is “scientifically defensible, consistent with the agency's statutory mission, and responsive to the needs of decision-makers” “Where alternative approaches with significant biological support are available for the same tumor response and no scientific consensus favors a single approach [i.e., no MOA], an assessment may present results based on more than one approach.” One procedure may be given greater weight or preference.

38. Evolution with Experience Implementation memo on web site Implementation working group Mutagenic MOA working group Examples will be posted on the web site

39. If you do something once, people will call it an accident. If you do it twice, they call it a coincidence. But do it a third time, and you’ve just proven a natural law. Admiral Grace Murray Hopper Inventor of the computer compiler, and distributor of nanoseconds

40. More than One MOA Both linear and nonlinear approaches may be used when there are multiple MOAs. If there are multiple tumor sites, then the appropriate extrapolation is used at each site. If there are multiple MOAs at a single tumor site, then both approaches can be used to decouple and consider the respective contributions of each MOA in different dose ranges.

41. More than One WOE Different descriptors for different routes of exposure, exposure levels, or MOA Narrative should describe the key decisions made and their significant biological support

42. Summary: Cancer Guidelines Emphasis on mode of action (MOA) Weight-of-evidence narrative and descriptors Two-step approach to dose-response assessment Choice of linear or nonlinear extrapolation

43. Take-home Lessons for Supplemental Guidance Numerous definitions of mutagenic and genotoxic exist Just because it is mutagenic, doesn’t mean it has a mutagenic MOA for carcinogenesis as described by the cancer guidelines and supplemental guidance Weight-of-the-evidence approach given wide variety of data sets

44. Take-home Lessons (cont.) Initial decision criteria  Cancer potency factor available  Weight of the evidence for mutagenic MOA; low-dose linearity  No chemical-specific carcinogenicity data exist  Apply age-dependent adjustment factors (ADAFs) if exposures are expected for the appropriate age groups

45. Take-home Lessons (cont.) If carcinogenicity data exist for early- life exposures for a chemical, use the chemical-specific data For all chemicals analyzed for the ADAFs in the supplemental guidance, chemical-specific data exist

46. Examples Consistent with 2005 Cancer Guidelines Chloroform: nonlinear extrapolation based on MOA http://www.epa.gov/iris/subst/0025.htm Not relevant to humans  α−2μ-globulin and kidney cancers: different kidney protein http://cfpub.epa.gov/ncea/raf/recordisplay.cfm?deid=54883  2-butoxyethanol (EGBE): concentrations not sufficiently high for sufficient hemolysis Gift, 2005. Toxicol. Lett. 156:163-178

47. Also Consistent (cont.) Linear and/or non-linear extrapolation: Thyroid follicular cell tumors http://cfpub.epa.gov/ncea/raf/recordisplay.cfm?deid=13102  Linear if mutagenic; nonlinear if not mutagenic; both demonstrates mutagenic and anti-thyroid effect  Five criteria required, additional desirable, for anti-thyroid MOA

48. When All Else Fails, Read the Instructions http://www.epa.gov/cancerguidelines http://www.epa.gov/iris Risk Assessment Forum http://cfpub.epa.gov/ncea/raf/index.cfm National Center for Environmental Assessment http://cfpub.epa.gov/ncea/